1. Field of the Invention
The invention relates to an aspartame preparation process. More particularly, the invention relates to a process and an apparatus for the recovery of raw materials from aqueous process streams that contain dissolved salt with use of a nanofiltration membrane.
2. Description of Related Art
Aspartame is an .alpha.-dipeptide ester, L-aspartyl-L-phenylalanine methyl ester ("APM"). APM is an important synthetic low-calorie sweetening agent that is about 200 times as sweet as sugar and has an exceptionally good taste pattern without, for instance, a bitter aftertaste. The sweetener is used in a wide range of products such as soft drinks, sweets, table-top sweeteners, pharmaceutical products and the like.
Aspartame can be prepared by various routes. There exist, for instance, routes whereby (N-protected) L-aspartic acid or the anhydride thereof and (L-)phenylalanine or the methyl ester thereof are chemically coupled. Optionally, the protecting group is removed later, and APM is obtained by esterification. An example of such a process is described in, for instance, U.S. Pat. No. 3,786,039.
Enzymatic processes exist whereby, for instance, N-protected L-aspartic acid and (DL-)phenylalanine methyl ester are selectively coupled to form the LL-dipeptide derivative and subsequently converted to APM. Such a process is described in, for instance, U.S. Pat. No. 4,116,768.
Raw materials often used in the manufacture of APM include: (1) L-aspartic acid ("Asp"), (2) L-aspartic anhydride ("AspAnh"), (3) N-protected derivatives thereof with protecting groups such as formyl ("F") and benzyloxycarbonyl ("Z"), for instance F-AspAnh and Z-Asp, and (4) L- or DL-phenylalanine ("Phe") and the methyl ester thereof ("PM"). These raw materials are not fully converted in the aspartame preparation processes. In addition, these might be reformed from decomposition during downstream steps of the preparation process.
In addition, other decomposition products such as, for example, 3-benzyl-6-carboxymethyl-2,5-diketopiperazine ("DKP") or L-aspartyl-L-phenylalanine ("AP") can be formed in downstream steps in the preparation process for APM. Still other undesired by-products can be formed, including the .beta.-form of APM (.beta.-APM) and products in which the free aspartyl carboxyl group of the dipeptide or dipeptide ester has been esterified. The latter dipeptide esters are also referred to as AP(M) and APM.sub.2.
For reasons of process economy, aspartame processes generally involve a large number of recirculation streams. During the preparation and work-up of aspartame, the various process streams undergo pH changes resulting from the addition of acids and bases. These changes result from, among other things, the addition of acids and bases for the removal of protecting groups. Also, pH changes can result from addition of acids and bases for purification, or for precipitation of, for instance, the Z-APM.PM addition product or the APM.HCl salt or any other addition product or crystallizing salt, or for recovery of APM by crystallization at a pH of 4.0 to 5.5.
The result is that various process streams contain inorganic salt or salts in addition to the starting materials and/or decomposition products already mentioned. In general, the process streams are aqueous, although the process streams may also contain organic solvents. Sodium chloride, for instance, is often present in amounts greater than about 1 wt. %, and very often in amounts as large as 10 or 25 wt. %. Streams of enzymatic processes may in addition contain small amounts of enzyme.
Various methods of recovering raw materials and/or removing decomposition products from process streams of aspartame preparation have been suggested or described. For instance, EP-A-0,476,875 describes methods for purification and concentration of biologically active materials from mixtures that contain organic solvents using solvent-stable membranes. Membrane processes are described in EP-A-0,476,875 which may be considered as "nanofiltration" membrane processes, using recent terminology. However, the term "nanofiltration" is not used in the specification, and the specification is not focused on the separation of low molecular weight organic compounds from salts.
EP-A-0,476,875 describes examples of concentrating very dilute (only 500 ppm) aqueous solutions of APM with use of membranes. However, there is no teaching or suggestion that such concentrating steps with use of membranes could be used favorably for treating dilute or concentrated APM solutions that contain amounts of salt higher than 2,000 ppm. In other words, EP-A-0,476,875 does not describe an effective method for treatment of aspartame solutions in the presence of high amounts of salt. The membranes of this reference appear to have high retention for salts; retention of salt is about 80% as calculated from the Examples. Accordingly, the membranes appear ill-suited for lowering the amount of salt in the retentate.
Other serious limitations for the process described in EP-0-476,875 exist. For example, it is evident from the examples on purification of penicillin G that the performance of the solvent-stable membranes does not vary over a broad range of pH values (from 0.5 to 12). However, performance sharply deteriorates at higher pH.
Other membrane processes related to the aspartame preparation process are known. For instance, EP-A-0,313,100 describes an electrodialysis process in which organic acids such as DKP and AP are removed.
According to JP-A-62-153,298, APM can be purified from low-molecular weight electrolytes by a dialysis process. A solution of APM in water at a pH of 3-7 and a temperature of 0.degree.-80.degree. C. was contacted with an amphoteric ion exchange membrane that allowed the low-molecular weight electrolytes to pass. The volume of the original solution was retained. In this type of process, an increase in pressure does lead to a desired increase in concentration. However, it also leads to unwanted permeation losses of organic products. Moreover, in a dialysis process, the dialyzate always needs to be replaced, which is quite cumbersome.
Also, EP-B-0,248,416 describes a salt removal process which--at elevated pressure--operates on the principle of reverse osmosis. That process utilizes neutral membranes such as polyamide acetate, polysulfone acetate and cellulose acetate membranes with 30-80% salt retention. At a lower salt retention, such membranes are not suitable because too much organic material will be transported. Hence, there will be no fractionating effect with respect to molecules larger than 100 D, wherein D is Dalton, or 1/16th the mass of the oxygen-16 isotope. Moreover, in such a reverse osmosis process, the extent to which the starting solution can be concentrated is limited inasmuch as the osmotic pressure strongly increases during the process.
The raw materials and other products still to be recovered often are present in relatively dilute streams. The presence of salt in the streams, however, makes it difficult to concentrate the streams by evaporation. Given the unfavorable weight ratio of organic components and salt, evaporation is expected to result in salt crystallization or cocrystallization with organic components. Moreover, undesired side-reactions may take place, which can result in strong discoloration.
None of these work-up processes has been found to be generally suitable for recovering raw materials from those aqueous process streams in the aspartame preparation processes which contain relatively high amounts--at least 1 wt. %--of salt. Moreover, processes such as dialysis or electrodialysis, reverse osmosis and treatment with an ion exchanger are relatively cumbersome and undesirable on an industrial scale. Furthermore, in many of the prior art methods, the solution started from can be concentrated only to a limited extent.
As a consequence, those skilled in the art have had a need for a process that does not suffer these drawbacks and enables the raw materials under consideration to be recovered easily and efficiently in a process involving simultaneous salt removal from the process streams and concentration of the organic components in them.
A general review of membrane technology can be found in the article entitled "Membranes and Membrane Separation Processes" found in Ullmann's Encyclopedia of Industrial Chemistry (VCH, 1990). Also, nanofiltration membrane technology is described in Chemical Engineering Progress, pgs. 68-74 (March, 1994).